Between 1930 and 1990, several dozen high-penetrance, predominantly monogenic disorders were identified and characterized, which led some investigators to speculate that individualized drug treatment was just around the corner. Informative DNA tests were sought to determine genetic predisposition to toxicity and cancer, thereby identifying individuals in which a drug was likely to be effective and those at increased risk of drug toxicity. These assays represent the leading edge of phenotype-genotype association studies, which are a major goal of clinical pharmacology and pharmacogenomics. Because of the complexity of the genome, however, the task is more challenging than anticipated originally. In the past decade we have come to appreciate how difficult it is to determine unequivocally either an exact phenotype or genotype. In the near future it seems unlikely that, by themselves, either transcriptomics or proteomics will be particularly helpful in achieving individualized drug therapy. However, recent advances in metabonomics are exciting and show promise. In the future, and perhaps in combination with proteomics, metabonomics might complement genomics in achieving personalized drug therapy.